EP0850234B1 - Novel heterocyclic compounds for the treatment of pain and use thereof - Google Patents

Novel heterocyclic compounds for the treatment of pain and use thereof Download PDF

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Publication number
EP0850234B1
EP0850234B1 EP96921855A EP96921855A EP0850234B1 EP 0850234 B1 EP0850234 B1 EP 0850234B1 EP 96921855 A EP96921855 A EP 96921855A EP 96921855 A EP96921855 A EP 96921855A EP 0850234 B1 EP0850234 B1 EP 0850234B1
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Prior art keywords
compound
methyl
heptahydro
alkyl
thia
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German (de)
English (en)
French (fr)
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EP0850234A1 (en
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John Dimaio
Dilip M Dixit
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Shire Canada Inc
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Shire BioChem Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/08—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/16—Eight-membered rings
    • C07D313/20—Eight-membered rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/16—Eight-membered rings

Definitions

  • the present invention relates to novel polycyclic opioid receptor agonists having analgesic activity and pharmaceutical acceptable compositions thereof.
  • the invention relates to methods and uses relating to the novel agonists and compositions.
  • Narcotic opiate analgesics remain the mainstay of presently available drug regimens used to alleviate moderate to severe pain.
  • Opiate analgesics produce a characteristic antinociceptive response in various animal species (including homo sapiens ) through activation of specific receptors in the central nervous system. It is well established that activation of one or more of these receptors produces antinociceptive effects in relevant animal models of pain assessment.
  • opioid receptors Multiple types have been shown to coexist in higher animals, of which at least three distinct classes have been characterized, with evidence for additional classes or subclasses: mu ( ⁇ ), kappa (K) and delta ( ⁇ ). For example, see W. Martin et al., J. Pharmacol. Exp. Ther., 197, p. 517(1975); and J. Lord et al., Nature (London), 257, p. 495 (1977).
  • the ⁇ receptor is located in the brain and appears to be involved in the analgesic effect of morphine-like drugs.
  • ⁇ -Receptor activation in the brain and spinal cord appears capable of producing analgesia, particularly at the spinal level.
  • ⁇ -receptor is found in some peripheral tissues in addition to the brain and spinal cord, and shows a differentiating affinity for endogenous opioid peptides known as enkephalins.
  • enkephalins endogenous opioid peptides known as enkephalins.
  • the present invention provides for compounds having analgesic activity which are novel polycyclic opioid receptor agonists having the general structure represented by formula I. wherein
  • a method of agonizing opioid receptors in a mammal comprising administering to said mammal an opioid receptor agonizing amount of a compound according to formula (I).
  • the compounds of formula (I), depending on the substituents, may contain one or more chiral centers and thus exist in the form of many different isomers, optical isomers (i.e. enantiomers) and mixtures thereof including racemic mixtures. All such isomers, enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention.
  • the invention also provides for pharmaceutically acceptable compositions comprising compounds of formula (I), for use in the management of pain.
  • compositions comprising compounds of formula (I), for use as diagnostic aids and/or research tools such as radioligands, radiotracers with Positron Emission Tomography or paramagnetic agents for use with Magnetic Resonance Imaging for opiate receptor mediated processes.
  • the invention further provides the use of a compound of Formula (I) for the manufacture of therapeutic agents for the management of pain.
  • the invention further provides the use of a compound of Formula (I) for the manufacture of chemical compounds for use as diagnostic aids and/or research tools such as radioligands, radiotracers with Positron Emission Tomography or paramagnetic agents for use with Magnetic Resonance Imaging for opiate receptor mediated processes.
  • a compound of Formula (I) for the manufacture of chemical compounds for use as diagnostic aids and/or research tools such as radioligands, radiotracers with Positron Emission Tomography or paramagnetic agents for use with Magnetic Resonance Imaging for opiate receptor mediated processes.
  • Figure 1 indicates dose dependent inhibition of the latency response to radiant heat by compound #9 administered subcutaneously to mice.
  • Figure 2 shows dose dependent inhibition of the writhing response (PBQ) by compound #9 administered orally to mice.
  • Figure 3 depicts dose dependent inhibition of the writhing response (PBQ) by compound #9 administered subcutaneously to mice.
  • ED 50 as shown in Table 1 for the PBQ writhing assay is defined as the dose of drug which induces a 50% reduction in the number of writhes observed compared to the control.
  • ED 50 used in the hot-plate assay ( Figure 1) is defined as the dose of drug required to increase the latency of response 2-fold compared to controls and was determined by log-probit analysis.
  • K i is the binding inhibition constant.
  • K i ⁇ /K i ⁇ is a value that may be used to measure selectivity. This ratio represents the relationship of the affinities of compounds for binding to the ⁇ - and ⁇ -receptors.
  • 'alkyl' represents a saturated or unsaturated, substituted (by a halogen, hydroxyl, amino, or C 6-20 aryl) or unsubstituted; straight chain, branched chain, or cyclic hydrocarbon moiety wherein said straight chain, branched chain, or cyclic hydrocarbon moiety can be interrupted by one or more heteroatoms (such as oxygen, nitrogen or sulfur).
  • heteroatom as used hereinafter represents N, O and S as well as SO and SO 2 .
  • 'aryl' represents a carbocyclic moiety which may be substituted (e.g. C 1-6 alkyl, halogen, hydroxyl, amino), interrupted by at least one heteroatom (e.g., N, O or S) and containing at least one benzenoid-type ring (e.g. phenyl and naphthyl).
  • 'aralkyl' represents an aryl group attached to the adjacent atom by an alkyl (e.g. benzyl).
  • the compounds of the present invention are represented by Formula (I) as defined above.
  • R 1 is cyclohexyl
  • R 1 is phenyl optionally substituted with polar groups.
  • Preferred polar groups are COOH, NH 2 or guanidine. More preferably, R 1 is H. Most preferably, R 1 is CH 3 .
  • R 2 is H.
  • R 3 is OH. Most preferably, R 3 is H.
  • R 4 is OCH 3 .
  • R 4 is OH.
  • n is 0.
  • m is 3.
  • a preferred compound of the invention includes: Compound #8b: 5, 6, 7, 8, 9, 11, 12- heptahydro -3-methoxy -5- methyl -10-thia -5, 11- methanobenzocyclodecene-13- amine.
  • a preferred compound of the invention includes: Compound #9: 5, 6, 7, 8, 9, 11, 12- heptahydro -3- hydroxy - 5- methyl -10- thia -5, 11- methanobenzocyclodecen -13- amine (sulphazocine).
  • a preferred compound of the invention includes: Compound #10: 5, 6, 7, 8, 9, 11, 12- heptahydro -3-hydroxy -5- methyl -10- thia -5, 11-methanobenzocyclodecene -13- hydroxylamine.
  • a preferred compound of the invention includes: Compound #9a (-)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine;
  • a preferred compound of the invention includes: Compound #11 trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-guanidine
  • a preferred compound of the invention includes: Compound #12 trans-5,6,7,8,9,11,12-heptahydro-10-sulphono-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine
  • More preferred compounds of the invention include:
  • Most preferred compound of the invention include:
  • the preferred compounds of the present invention can be synthesized using conventional preparative steps and recovery methods known to those skilled in the art of organic and bio-organic synthesis, while providing new and unique combinations for the overall synthesis of each compound.
  • Preferred synthetic routes for intermediates involved in the synthesis as well as the resulting compounds of the present invention follow. Successful preparation of these compounds is possible by way of several synthetic routes one of which is outlined in Scheme 1.
  • Step 1
  • Compound I an alkyl-1-tetralone
  • an appropriate Grignard Reagent such as methyl magnesium bromide in a dry non-polar solvent such as THF, to generate the tertiary alcohol, Compound II.
  • Step 2
  • the alcohol, Compound II is dehydrated under acidic conditions, such as aqueous saturated NH 4 Cl, to yield Compound III.
  • the double bond at position 1 on the olefin is epoxidized using standard reagents and solvents, such monoperoxyphthalic acid magnesium salt in isopropanol, to produce the epoxide, Compound IV.
  • Step 4
  • the epoxide is rearranged under acidic conditions, such as aqueous NaHCO 3 , using standard techniques to generate the ketone, Compound V.
  • Nucleophilic displacement of bromide is accomplished with an appropriate acylating agent, such as potassium thiacetate to produce Compound VII.
  • the 3 position of the acylated tetralone (Compound VII) is halogenated in a non-polar solvent, such as a mixture of benzene and dry THF, using an appropriate reagent and non-polar solvent such as Bromine in dry THF to generate Compound VIII.
  • a non-polar solvent such as a mixture of benzene and dry THF
  • the side chain is cyclized under basic conditions using standard reagents and solvents such as lithium bromide and dry THF under Argon, with the addition of a base such as sodium methoxide, generating the polycyclic compound (Compound IX).
  • ketone group of compound IX is converted to an alkyloxime using standard procedures well known in the art affording compound X.
  • Compound X is reduced using a Borane-THF complex. If conducted in THF, a 50:50 mixture of compounds XI and XII is obtained. If the reaction is conducted in diglyme (2-methoxyethyl ether), the amine, (Compound XII) is selectively produced.
  • Compound XI can be recycled and reduced to the amine using a Borane-THF complex conducted in diglyme to yield Compound XII.
  • the compounds of the present invention can be modified by one skilled in the art in such a manner as to attach labels such as radioactive labels enabling detection of the compound for use as a radiotracer.
  • the compounds of the present invention may be used as agonists at the opiate receptor in vitro or ex vivo as in the case of radio-labeling agents, radiotracers for use with Positron Emission Tomography, paramagnetic agents for use in Magnetic Resonance Imaging, and NMDA receptor-linked calcium channel antagonists.
  • the compounds of the present invention can be modified by one skilled in the art in such a manner as to prevent access into the central nervous system such that they can function as opiate receptor agonists in peripheral tissues.
  • the present invention also provides pharmaceutical compositions which comprise a pharmaceutically effective amount of the compounds of this invention, or pharmaceutically acceptable salts thereof, and, preferably, a pharmaceutically acceptable carrier or adjuvant.
  • pharmaceutically effective amount is the amount of compound required upon administration to a mammal in order to induce analgesia.
  • opioid receptor agonizing amount refers to the amount of compound administered to a mammal necessary to bind and/or activate opioid receptors in vivo.
  • Therapeutic methods of this invention comprise the step of treating patients in a pharmaceutically acceptable manner with those compounds or compositions.
  • Such compositions may be in the form of tablets, capsules, caplets, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • the therapeutic agents of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers.
  • the proportion of each carrier is determined by the solubility and chemical nature of the compound, the route of administration, and standard pharmaceutical practice.
  • a composition of the invention is in the form of a unit dose.
  • the unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients.
  • binding agents such as acacia, gelatin, sorbitol, or polyvinylpyrolidone
  • fillers such as lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants such as magnesium stearate
  • disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose
  • pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • the compounds may be injected parenterally; this being intramuscularly, intravenously, or subcutaneously.
  • the compound may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic.
  • the compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like.
  • the compounds may be administered orally in the form of solutions which may contain coloring and/or flavoring agents.
  • the compounds may also be administered sublingually in the form of tracheas or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form.
  • the solid oral compositions may be prepared by conventional methods of blending, filling, tabletting, or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Oral liquid preparations may be in the form of emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may or may not contain conventional additives.
  • suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fats
  • emulsifying agents such as sorbitan monooleate or acaci
  • non-aqueous vehicles which may include edible oils), such as almond oil, fractionated coconut oil, oily esters selected from the group consisting of glycerine, propylene glycol, ethylene glycol, and ethyl alcohol
  • preservatives for instance methyl para-hydroxybenzoate, ethyl parahydroxybenzoate, n-propyl parahydroxybenzoate, or n-butyl parahydroxybenzoate of sorbic acid; and
  • fluid unit dosage forms may be prepared by utilizing the compound and a sterile vehicle, and, depending on the concentration employed, may be either suspended or dissolved in the vehicle.
  • the compound Once in solution, the compound may be injected and filter sterilized before filling a suitable vial or ampoule and subsequently sealing the carrier or storage package.
  • Adjuvants such as a local anesthetic, a preservative or a buffering agent, may be dissolved in the vehicle prior to use. Stability of the pharmaceutical composition may be enhanced by freezing the composition after filling the vial and removing the water under vacuum, (e.g., freeze drying the composition).
  • Parenteral suspensions may be prepared in substantially the same manner, except that the compound should be suspended in the vehicle rather than being dissolved, and, further, sterilization is not achievable by filtration.
  • the compound may be sterilized, however, by exposing it to ethylene oxide before suspending it in the sterile vehicle.
  • a surfactant or wetting solution may be advantageously included in the composition to facilitate uniform distribution of the compound.
  • compositions of this invention comprise a pharmaceutically effective amount of a compound of this invention and a pharmaceutically acceptable carrier. Typically, they contain from about 0.1% to about 99% by weight, preferably from about 10% to about 60% by weight, of a compound of this invention, depending on which method of administration is employed.
  • the present invention also provides a method for management of pain in patients, such as mammals, including humans, which comprises the step of administering to the patient a pharmaceutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.
  • Physicians will determine the dosage of the present therapeutic agents which will be most suitable. Dosages may vary with the mode of administration and the particular compound chosen. In addition, the dosage may vary with the particular patient under treatment. The dosage of the compound used in the treatment will vary, depending on the seriousness of the disorder, the weight of the patient, the relative efficacy of the compound and the judgment of the treating physician. Such therapy may extend for several weeks, in an intermittent or uninterrupted manner, until the patient's symptoms are eliminated.
  • the compounds of the present invention may be used as opiate receptor agonists in vitro or ex vivo as in the case of, for example, radio-labeling agents, radiotracers, paramagnetic agents.
  • the compounds of the invention may be used as research tools and/or diagnostic aids.
  • Dihydro -7- methoxy -4- methylnaphthalene (20.87 g) was dissolved in isopropanol (100 ml) and cooled in an ice bath. Monoperoxyphthalic acid magnesium salt (mmpp) (17 g) was added, then water (50 ml) was added and the mixture was stirred at room temperature for 2 hours. When oxidation was complete, the product mixture was hydrolyzed with aqueous NaHCO 3 , partially evaporated and extracted with ethylacetate. The latter extract was washed with brine and evaporated. The residue was dissolved in a mixture of ethanol (156 ml), water (121 ml) and conc.
  • the residue was basified with concentrated NH 4 OH to pH 12, extracted with CH 2 Cl 2 , washed with brine, dried over MgSO 4 and evaporated.
  • the residue was purified on a silica gel column using a mixture of hexanes and ethylacetate (50:1, 20:1, 10:1, 5:1, 5:1.5, 2:1, 1:1 and 1:2).
  • the yield of 5, 6, 7, 8, 9, 11, 12 - heptahydro-3- methoxy -5- methyl-10- thia -5.11- methanobenzocyclodecen -13- hydroxylamine was 0.073 g (23.1%). It was crystallized from a mixture of ethylacetate and hexanes.
  • Mass Spectrometry 293.8, 275.8, 260.8.
  • the tartrate salt of the title compound (0.1g) was dissolved in hot methanol (20mL) and transferred to a column packed with Amberlite IRA-400 (Cl - form) ion exchange resin (5g, washed successively with methanol, water, 0.1M HCl, water and methanol). The column was washed with methanol (100mL) and water (100mL) in succession. Combined eluents were evaporated off and lyophilized. Residue (0.076g)
  • Compound #9-D-tartrate salt (highly enriched in dextrorotatory diastereomer 1.5g) was mixed with NH 4 OH (10mL) saturated with sodium chloride and extracted with methylene chloride. The latter was washed with brine, dried over MgSO 4 and evaporated. Residue (1.27g) was mixed with L-tartaric acid (0.87g) and boiled with ethanol (95%, 100mL) filtered, the filtrate then being allowed to crystallize at room temperature for 2 days. The precipitated mass was allowed to crystallize slowly from hot isopropanol. A sample was found to have a diastereomeric purity of 97% via chiral derivatization with Marfey's reagent to give 0.1515g yield.
  • Residue was purified on a silica gel column using a mixture of hexanes and methylene chloride to yield 0.068g of trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-trifluoroacetamide.
  • Antinociceptive activity of compounds of the invention was determined in vivo in a PBQ writhing model and in the hot plate test in rodents. Inhibition of PBQ (phenyl- ⁇ -benzoquinone) induced writhing in mice is an assessment of both central and peripherally-mediated analgesia. For experimental protocol see Sigmund et al., Proc. Soc. Ex. Biol. Med., 95 , p. 729 (1957) which is incorporated herein by reference. Centrally-mediated analgesia was determined by the inhibition of a hot plate response in mice. For experimental protocol see G. Woolfe and A. Macdonald, J. Pharmacol. Exp. Ther., 80 , p.
  • Radioligand 50 ⁇ l, membranes 100 ⁇ l and serially diluted test compound were incubated for 1 hr at 22°C. Non specific binding was determined using 500 fold excess of unlabeled ligand in the presence of tracer and membranes. Free ligand was separated from bound by filtration through Whatman GF/B paper (presoaked in polyethylenimine 1% aqueous solution) and rinsing with ice-cold 50mM Tris pH 7.4 using a Brandel cell harvester. The filters were dried and radioactivity was counted in a 24 well microplate in the presence of 500 ml scintillant per well. Radioactivity was measured using a Wallac 1450 Microbeta counter.
  • Displacement curves were drawn using Microsoft Excel program.
  • the Ki's for the various compounds were determined from the IC 50 according to the Cheng and Prusoff equation. Receptor binding and in vivo inhibitory activity of test compounds in the PBQ assay (mice) ED 50 mg/kg Compound Ki ⁇ nM (DAMGO) K i ⁇ nM (DADLE) K i ⁇ nM s.c. p.o.
  • the test was performed using CD #1 male mice (Charles River) weighing between 19 and 25 g. Animals were maintained in constant conditions of light, temperature and humidity. The animals were acclimatized for three days prior to experimentation.
  • a solution of phenylquinone (0.02%) was prepared in the following fashion. 20 mg of phenylquinone was dissolved in 5 ml ethanol 90%. The phenylquinone solution was slowly added to 95 ml of distilled water with continuous stirring and gentle heating. The phenylquinone solution was protected from light at all times and a new solution was prepared every day for the test. It is recommended to wait 2 hours before using the phenylquinone solution.
  • test compounds were dissolved in distilled water and administered subcutaneously or by oral gavage.
  • mice were injected, by intraperitoneal route, with a solution of 0.02% phenylquinone (2-phenyl-1,4-benzoquinone, Sigma).
  • the phenylquinone was injected at various time intervals of 20, 60, 120 and 180 minutes after administration of the compound (or vehicle, or standard).
  • mice Male mice (Charles River) weighing between 20-25 grams were used. The mice were weighed, identified, and randomized into groups of 10.
  • mice were usually treated by subcutaneous injection of the compound (or the standard or vehicle) or by oral gavage.
  • mice were evaluated individually for a latency reaction time on the hot plate.
  • the temperature of the hot plate (Sorel, model DS37) was set at 55 °C.
  • the mice were observed for signs of discomfort such as licking or shaking of the paws, attempting to escape (jumping off the plate) or trembling.
  • the reaction time was recorded when one of these signs was noted.
  • the cut off for latency response was 15 seconds so as to prevent damage to the paw tissue.
  • analgesic time course the mice were observed at different time intervals following administration of the compound (or vehicle, or standard). The time intervals are typically 30, 60 or 120 minutes (or other).
  • the average reaction time of the control group was multiplied by 1.5.
  • the reaction time of each treated animal was compared to the "control average X 1.5". If the reaction time was inferior to the "control average X 1.5", the mouse was considered not to have had an analgesic effect. If the reaction time was superior to the "control average X 1.5" then the mouse was considered to have had an analgesic effect. If the percentage of mice rendered analgesic was less than 30%, the compound was considered inactive.
  • Figures 1 - 3 show the antinociceptive effects of compound #9 in mice by evaluating the reaction of the mice in the hot plate test and inhibition of the writhing response in the PBQ assay.
  • Figure 2 shows the inhibition of the writhing response elicited in mice by oral administration of compound #9 pne hour prior to PBQ administration
  • Figure 3 demonstrates inhibition of the writhing response elicited in mice by s.c. administration of compound #9, twenty minutes prior to PBQ administration.

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EP96921855A 1995-07-14 1996-07-12 Novel heterocyclic compounds for the treatment of pain and use thereof Expired - Lifetime EP0850234B1 (en)

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GBGB9514417.6A GB9514417D0 (en) 1995-07-14 1995-07-14 Novel heterocyclic compounds for the treatment of pain and use thereof
GB9514417 1995-07-14
PCT/CA1996/000467 WO1997003978A1 (en) 1995-07-14 1996-07-12 Novel heterocyclic compounds for the treatment of pain and use thereof

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WO1997003978A1 (en) 1997-02-06
FI974609A (fi) 1998-01-14
JPH11509211A (ja) 1999-08-17
US6054474A (en) 2000-04-25
HUP9900350A2 (hu) 1999-06-28
BR9609548A (pt) 1999-03-02
AU708504B2 (en) 1999-08-05
NO980144D0 (no) 1998-01-13
NO980144L (no) 1998-01-13
DE69617444D1 (de) 2002-01-10
EP0850234A1 (en) 1998-07-01
ES2167577T3 (es) 2002-05-16
CN1196053A (zh) 1998-10-14
AU6296896A (en) 1997-02-18
EA001185B1 (ru) 2000-12-25
FI974609A0 (fi) 1997-12-23
EA199800062A1 (ru) 1998-08-27
NZ311612A (en) 1999-05-28
DE69617444T2 (de) 2002-08-01
CA2223646A1 (en) 1997-02-06
GB9514417D0 (en) 1995-09-13
ATE209643T1 (de) 2001-12-15
HUP9900350A3 (en) 1999-11-29

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